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[Duration of viremia and fecal shedding of the virus in hepatitis A infected children].

Hepatitis A virus (HAV) infection is endemic in Argentina. Molecular tools have allowed HAV RNA detection to be extent to sera and feces from patients with different clinical backgrounds. We compare the sensitivity of the RT-PCR protocol we follow using primers targeting different genomic regions and VP3 C terminal was the most sensitive. Sequential sera and fecal samples were obtained from 20 children with acute self limited Hepatitis A. HAV RNA was detectable in 18/20 children if sera and stool specimens were collected at the onset of symptoms and in 19/20 if a later sample was considered. HAV RNA was detectable in serum from 9/20 patients until day 30 and in feces from 2 patients until day 60 and until day 90 in one. Genomic sequences from VP1/2A region in 8 samples showed they all belong to subgenotype IA although they were different between them. HAV RNA was detectable only in 1/11 sera from children with acute liver failure when VP3 C terminal fragment was searched and it belonged to genotype I. Universal vaccination in one year old children was recently implemented in Argentina and it will dramatically enable the decrease of the viral circulation, making new sources of infection emerge and allowing the introduction of new genotypes. The application of molecular tools to the study of the natural history of infection and to the epidemiologic surveillance may contribute to efficient control and lead to rational decisions in public health policies.

Acute Disease↗

Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.

The long-term effect of interferon alfa (IFN-alpha) in Chinese patients with chronic hepatitis B infection is unknown. A total of 411 chronic hepatitis B patients (208 treated with IFN-alpha and 203 as control) were followed up for hepatitis B serology and the development of hepatoma and other cirrhosis-related complications. The hepatitis B e antigen (HBeAg) seroconversion rate in the IFN-alpha-treated group, though significantly greater at 6 and 24 months, was comparable with the control group on subsequent follow-up, irrespective of pretreatment alanine transaminase (ALT) levels. HBeAg seroreversion rate was higher in the IFN-alpha group compared with the control group (21.1% vs. 2.2%; P =.001). Loss of hepatitis B surface antigen (HBsAg) occurred in 2.4% of the IFN-alpha-treated patients and 0.49% of the control patients (P = NS). Around 90% of the anti-HBe-positive patients in both groups were still hepatitis B virus (HBV)-DNA-positive by polymerase chain reaction (PCR) assay. Two patients suffered from hepatic reactivation during the course of treatment. Nine (4.3%) patients in the IFN-alpha group and 2 (1.0%) in the control group developed complications of cirrhosis and hepatoma (P =.062). In Chinese HBsAg carriers, IFN-alpha was of no long-term benefit in inducing HBeAg seroconversion or in the prevention of hepatoma and other cirrhosis-related complications.

Adolescent↗

Comparison of different treatment combinations for chronic hepatitis B infection.

Chronic hepatitis B virus (HBV) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Its prevalence approaches 10% in hyper endemic areas. The aim of treating chronic HBV infection is to halt progression of liver injury by suppressing viral replication or eliminating infection. This study was planned to evaluate the advantages of combination therapy with interferon-alpha plus second-generation nucleoside analogues (lamivudine or famciclovir), or vaccination with a pre-S2 and S proteins containing vaccine in chronic HBV infection. 29 patients were divided into three groups and were treated with the following combinations: (1) IFN-alpha2a 9 million units 3x week for 6 months with HBV vaccine 20 microg given on 0, 1 and 2 months; (2) IFN-alpha2a 6 million units 3x week plus famciclovir 250 mg 3x day for 6 months; (3) IFN-alpha2a 6 million units 3x week plus lamivudine 100 mg/day for 6 months. Complete response was suspected in 3 patients in group 1, in 4 patients in group 2, and in 7 patients in group 3. Partial response was suspected in 4, 1 and 2 patients in groups 1, 2 and 3, respectively. The results of the present study suggest that the combination of IFN-alpha with lamivudine is more effective than the combination of IFN-alpha with HBV vaccination or famciclovir.

2-Aminopurine↗

Alterations in hepatic chromatin template availability during infection.

Hepatic chromatin was isolated from rats at various times after inoculation with either live or heat-killed bacteria. The chromatin was assayed under conditions that allow determination of the DNA template available to support in vitro transcription. Both a fulminant Diplococcus pneumoniae and a milder Salmonella typhimurium infection produced time-related increases in hepatic chromatin template availability when compared to chromatin isolated from rats inoculated with heat-killed bacteria. Both timing and magnitude of increased template availability correlated with the severity of the infection. The earliest change observed was a 50 percent rise in availability noted 4 h after inoculation with D. pneumoniae. This preceded the onset of fever, as well as other known heaptic consequences of systemic infection. After 24 h of infection the maximum rise of 90 percent occurred. Similar changes developed during S. typhimurium infection, but were slower in onset and smaller in magnitude. Adrenalectomy prior to infection enhanced the severity of the disease but markedly blunted the increase in template availability. The data are consistent with the hypothesis that systemic infection regulates the hepatic metabolic response to infection through transcriptional control and that a permissive or stimulatory action of glucocorticoids is involved in the increases in template availability effected.

Adrenalectomy↗

Hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for a substantial proportion of liver diseases worldwide. Because the two hepatotropic viruses share same modes of transmission, coinfection with the two viruses is not uncommon, especially in areas with a high prevalence of HBV infection and among people at high risk for parenteral infection. Patients with dual HBV and HCV infection have more severe liver disease, and are at an increased risk for progression to hepatocellular carcinoma (HCC). Treatment of viral hepatitis due to dual HBV/HCV infection represents a challenge.

Journal Article↗

Immune globulin and vaccine therapy to prevent hepatitis A infection.

The hepatitis A virus is usually transmitted person-to-person due to fecal-oral exchange of virus. Approximately 30,000 infections are reported each year in the United States, with the actual incidence being much greater. Prophylaxis with immune globulin has had a minimal impact on the overall incidence of hepatitis A. The recent availability and proven efficacy of a hepatitis A vaccine offers the hope that the incidence of infection may be substantially reduced. Pre- and postexposure prophylaxis should be targeted to individuals at increased risk of either acquiring infection, transmitting infection, or developing fulminant hepatitis, or to help control epidemics. This article reviews the current literature and discusses recommendations for pre- and postexposure prophylaxis against hepatitis A virus.

Adult↗

Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors.

BACKGROUND: The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc+ donors in recipients who are susceptible to de novo hepatitis B virus (HBV) infection. The efficacy of hepatitis B immune globulin and lamivudine to prevent de novo HBV infection in anti-HBs negative recipients of allografts from anti-HBc+ donors has not been investigated. METHODS: After liver transplantation with an allograft from a donor positive for anti-HBc, recipients who were anti-HBs-, HbsAg- received hepatitis B immune globulin (HBIG) 10,000 IU i.v. daily for 7 days and monthly for 6 months. After 6 months, 1000 IU of HBIG was given IM. every 2 weeks for 18 months. Patients transplanted after 4/1/97 were given lamivudine 150 mg daily starting postoperative day 1. RESULTS: Between 8/14/96 and 6/10/98, 264 orthotopic liver transplants were performed and 16 anti-HBs-, HbsAg- patients received an hepatic allograft from a donor positive for anti-HBc. HBIG mono-therapy was administered to one patient. HBIG and lamivudine combination therapy was administered to 15 patients. Of the 16 patients, 8 were positive only for anti-HBc before transplant, and 8 were naive (anti-HBs-, anti-HBc-). The single patient who received HBIG monotherapy became HbsAg+ at 6 months. All patients receiving combination therapy with HBIG and lamivudine have remained HbsAg-. The average follow-up is 459 days (range 170-754). Two patients died from unrelated causes. CONCLUSIONS: Combination therapy with HBIG and lamivudine may prevent de novo HBV infection in anti-HBs-, HbsAg- recipients of hepatic allografts from anti-HBc+ donors.

Hepatitis B↗

Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection.

To examine the role of hepatitis C virus (HCV) infection in spontaneous hepatitis B surface antigen (HBsAg) clearance during the course of chronic hepatitis B virus (HBV) infection, serum specimens from 32 asymptomatic HBsAg carriers and 22 patients with chronic hepatitis type B who underwent spontaneous HBsAg clearance were studied for antibody to HCV (anti-HCV) using commercial EIAs. The results were compared with those of control groups matched for age, sex, hepatitis B e antigen, antibody to hepatitis delta virus, and cirrhosis. Eight (25%) of the asymptomatic carriers and 9 (41%) of the patients with chronic hepatitis were seropositive for anti-HCV in contrast to 1.6% and 9.1% of their respective control groups (P less than .01). Serum alanine aminotransferase level was persistently abnormal after HBsAg clearance in one asymptomatic carrier and in four patients with chronic hepatitis. These patients were seropositive for anti-HCV and at least one of them was negative for HBV-DNA by polymerase chain reaction. The data suggest that HCV superinfection may not only suppress HBV or terminate the HBsAg carrier state but may also assume the role of HBV as the cause of persistent hepatitis or transaminase elevation.

Adult↗

Primary human hepatocytes in spheroid formation to study hepatitis C infection.

BACKGROUND: Hepatitis C (HCV) is a worldwide health problem, affecting nearly 170 million people. Current models for studying Hepatitis C have focused primarily on the use of poorly permissive cell lines and viral constructs, because of the lack of a suitable animal model or an in vitro system for studying functional infection. As hepatocytes are the primary reservoir for the virus in vivo, we report on a model using primary human hepatocytes cultured in spheroid formation. MATERIALS AND METHODS: The hepatocytes were harvested from uninfected liver resections and cultured as spheroids (that promotes a differentiated phenotype) or monolayers. Spheroids expressed the putative receptors CD81 and human scavenger receptor B1 in a variable pattern throughout the culture period. Samples were inoculated with infectious HCV serum, and HCV RNA was detected using RT-PCR. RNA was detected in the cells and culture medium by 3 days and 5 days after inoculation, respectively. Selection of HVR1 variants occurred in a differential pattern based on culture technique, suggesting that viral selection was dependent on host phenotype. Detection of NS5A by Western blot analysis of infected samples and immunofluorescence for HCV core protein was seen only in infected spheroids. CONCLUSION: The use of spheroid formation to study Hepatitis C is associated with the establishment of HVR1 selection and functional infection. This represents a promising alternative model to study Hepatitis C.

Antigens, CD↗

Management of chronic hepatitis B and C virus infections.

Hepatitis B and C virus (HBV and HCV) infections present an important health problem causing significant morbidity and mortality on a worldwide scale. The younger the subjects infected, the higher the risk predisposing to progression towards chronic infection. Treatment of chronic HBV and HCV infections is aimed at reducing hepatic inflammation and thus improving the symptoms, decreasing the likelihood of long-term sequelae such as hepatocellular carcinoma, and increasing the survival rate. Interferon accelerates the spontaneous course of chronic HBV infection in children with greater disease activity and lower levels of replication. There is limited information on the use of lamivudine and its long-term benefit in children with chronic HBV infection. The response of combination therapy with IFN and ribavirin in children with chronic HCV infection is still under investigation. The long-term clinical and virological effects of various drugs used in chronic HBV and HCV infections on children remain to be evaluated.

Adolescent↗

Peginterferon-alpha 2a (40 kDa)/ribavirin combination for the treatment of chronic hepatitis C infection.

Chronic hepatitis C is the leading cause of liver disease and liver-related mortality in the western world. Treatment of this chronic viral infection has considerably improved with the introduction of ribavirin-interferon combination therapy. Ribavirin (Copegus, Rebetol) is a synthetic nucleoside analogue with broad antiviral effects. It is absorbed readily upon oral administration with meals. Daily doses of up to 1200 mg are usually well-tolerated, causing dose-dependent haemolysis, reversible with dose reduction in most patients, in particular in those with renal insufficiency. In the circulation it is bound to erythrocytes, and eliminated by phosphorylation and deribolysation. The drug accumulates in blood with renal insufficiency. Impairment of hepatic function does not influence drug levels in the circulation. In animal studies, teratogenic and reproductive toxicity was shown. In chronic hepatitis C virus infection, monotherapy with ribavirin has no effect on concentrations of viral RNA or liver histology. Combination therapy with pegylated interferon-alpha2a (40 kDa) (Pegasys) produces significantly higher sustained virological response rates in infections with all viral genotypes, even in advanced stages of liver disease compared pegylated interferon-alpha2a monotherapy, adverse effects and quality of life are not significantly different.

Animals↗

Search for hepatitis delta virus (HDV) infection in hepatitis C patients in north-eastern Poland. Comparison with anti-HDV prevalence in chronic hepatitis B.

Hepatitis C virus and hepatitis D virus have been shown to suppress HBsAg synthesis. Thus it is possible that HDV infection occurs despite the lack of detectable HBsAg. The aim of our study was to (a) determine the prevalence of HDV infection in patients with chronic hepatitis C (b) compare it with the prevalence of HDV infection in HBsAg positive patients with hepatitis B. The study group consisted of 51 chronic hepatitis C patients, 30 HIV infected drug addicts (27 of them were also positive for anti-HCV) and 102 hepatitis B patients. The participants were tested for anti-HDV, anti-HCV and HBsAg. All anti-HCV positive patients were negative for anti-HDV. Four individuals with anti-HDV belonged to hepatitis B group and constituted 3.9% of all HBsAg positive subjects. We conclude that (a) there is currently no evidence of HDV infection among HCV infected patients in our region (b) hepatitis delta infection is rare in north-eastern Poland.

Adult↗

The three type of human viral hepatitis.

Infections with hepatitis A and B viruses are common in all parts of the world and constitute a major public health problem. The identification of specific antigenic markers of these viruses has led to the development of sensitive laboratory tests. These, in turn, have resulted in a better understanding of the epidemiology, pathogenesis, immunology, and the nature of these common infections. In the case of hepatitis type B, laboratory tests revealed a persistent carrier state of the surface antigen in some 120-175 million people and established the significance of hepatitis B virus in the pathogenesis of serious chronic liver disease, including a strong association with primary hepatocellular carcinoma in tropical and some subtropical regions. In addition, the specific diagnosis of hepatitis types A and B has revealed a previously unrecognized form of hepatitis which is clearly unrelated to either type. This new form of infection of the liver is now the most common type of hepatitis after the transfusion of blood and blood products in some areas of the world and it also appears to be an important cause of sporadic hepatitis, particularly among adults.

Animals↗

Pegylated interferon and ribavirin therapy for chronic hepatitis C virus genotype 4 infection.

Hepatitis C Virus (HCV) is classified into six genotypes. Genotype 4 is now spreading in Europe, especially among drug users, who are often infected with both HCV and the human immunodeficiency virus (HIV). Previous studies have shown that HCV-4 responds poorly to interferon. Pegylated interferon (peg-IFN) associated with ribavirin is now the most effective treatment for eradicating the virus. We have now studied the response of HCV-4 to peg-IFN and ribavirin and investigated the influence of HIV infection on anti-HCV therapy. Twenty-eight patients infected with HCV-4 were given peg-IFN plus ribavirin for 48 weeks. Patients infected with HCV alone tended to have a better initial response (66%) than patients infected with both HCV and HIV (30%, P = 0.06) and eradication was better (50%) than in doubly infected patients (15%, P = 0.06). After controlling for major factors influencing virus response, the virus response 12 weeks after the beginning of treatment in patients infected with HCV-4 (50%) was similar to that of patients infected with genotype 1 (53%) and lower than that of patients infected with genotypes 2 or 3 (82%, P < 0.05). The response 24 weeks after the end of therapy in patients infected with HCV-4 (32%) was similar to that of patients infected with HCV-1 (28%) and lower than that of patients with HCV-2 or HCV-3 (62% P < 0.05). These results indicate that HCV-4 patients should be considered to be difficult-to-treat.

Adult↗

Intrahepatic alpha beta-TcRintermediate LFA-1high T cells are stimulated during mouse hepatitis viral infection.

Mouse hepatitis virus type 3 (MHV3), a coronavirus, is an excellent animal model for the study of thymic and extrathymic T cell subpopulation disorders induced during the viral hepatitis. To understand local hepatic immune responses, the phenotypes of resident hepatic lymphocytes were determined and compared that of splenic and thymic T cell subpopulations during the acute viral hepatitis induced by MHV3 in susceptible C57BL/6 mice. Single positive (SP) CD4+ or CD8+ cells strongly increased in the liver. A specific cell population, the double positive (CD4+ C8+) cells, normally present in liver and thymic cell preparations, decreased in C57BL/6 mice following the viral infection. alpha beta-TcRintermediate T cells shifted toward alpha beta-TcRhigh T cells in the liver and thymus of infected mice, but not in their spleen. The specific alpha beta-TcRint or high lymphocytes occurring in the liver of MHV3-infected mice expressed higher levels of leukocyte function antigen-1 (LFA-1) and Pgp-1 (CD44) activation markers, suggesting that they were either activated or antigen-experienced during the viral infection. No significant changes in T cell subpopulations were detected in the spleen. These observations suggest that MHV3 infection could induce an early in situ stimulation of resident hepatic T cells, despite a peripheral immunodeficiency in the thymus and spleen.

Animals↗

Prior hepatitis A virus infection enhances acute hepatitis E virus infection.

The epidemiology and clinical manifestations of hepatitis E virus (HEV) and hepatitis A virus (HAV) are similar. However, two distinct diseases develop after exposure to each one of the viruses, which are apparently unrelated clinically. It is interesting to note that all reported epidemics and single cases of acute HEV infection indicate previous exposure to HAV. This fact leads us to hypothesize that acute HEV infection is dependent on past infection by hepatitis A virus, and that the sequential infections could not solely be explained on independent outbreaks. This hypothesis, where past HAV infection serves to support acute HEV infection, may have current practical implications, and could improve our understanding of the virology and pathophysiology of the disease.

Adolescent↗

Histological changes of concurrent hepatitis C virus infection in asymptomatic hepatitis B virus patients.

In chimpanzees and in vitro cell culture studies, hepatitis C infection has been shown to suppress hepatitis B virus expression. In addition, hepatitis C infection can cause much more severe liver disease in patients chronically infected with hepatitis B virus. The aims of the present study were to determine the prevalence of hepatitis C infection in asymptomatic chronic hepatitis B Hong Kong Chinese patients and the histological changes and hepatic expression of hepatitis B virus and hepatitis C virus. Five hundred and seventy-one Hong Kong Chinese asymptomatic chronic hepatitis B patients were studied. Only four (0.7%) were hepatitis C virus antibody positive; they were also all positive for hepatitis C viral RNA in serum by reverse transcription-polymerase chain reaction (RT-PCR). Portal lymphoid aggregates and bile duct damage was noted in the liver sections of three of the four patients. Hepatic expression of hepatitis B surface antigen was detected in three patients; none had detectable hepatitis B core antigen. By branched DNA assay, serum hepatitis B DNA could not be detected in any of the four patients, but three had hepatitis C RNA. By in situ RT-PCR, hepatitis C RNA was detected in the cytoplasm of three of the four patients. These findings suggest that hepatitis C coinfection in asymptomatic chronic hepatitis B patients is uncommon in Hong Kong Chinese and active hepatitis B viral replication is absent in these patients.

Adolescent↗